The goal of this project is to determine the mechanism for complement enhancement of the humoral immune response to herpes simplex virus-I (HSV-1) and to test the use Of C3 as a natural adjuvant in development of vaccines. Our (in collaboration with project 3) preliminary results have demonstrated that the immune response to HSV-1 is impaired in mice deficient in either C3 or its receptor CD21. This observation is important for several reasons. It is the first observation that the complement system enhances the immune response to herpes virus. Second, it demonstrates a novel mechanism for HSV-l evasion of the immune response, i.e. by blocking complement activation. Third, it demonstrates that activation products of C3, i.e. C3d, could be used as an adjuvant for an HSV vaccine. This project will define the mechanism for complement enhancement and determine how HSV-I evades the complement enhancing effect in the first alm. This aim will be performed in collaboration with project 3. The second and third alms will examine the importance Of local C3 synthesis and the effects C3 adjuvants have on B and T cell activation and tracking within the lymphoid compartment. Project 3 will provide the recombinant HSV-I virus for evaluating complement as a natural adjuvant in boosting the immune response. This project will interact with the first and second projects in analysis of complement enhancement of uptake and processing of antigen by antigen presenting cells. In summary, as a major mediator of the inflammatory response, complement provides an important adjuvant effect in the immune response to protein antigens. HSV-l evades this effect by inactivating C3 and limiting its covalent attachment. Clarifying the different stages in which complement is involved in the immune response to HSV, i.e. uptake and processing of antigen, upregulation of costimulators, B cell activation, antigen trapping, opsonization of virus in DH response, will be important for the design of complement related adjuvants in the absence of toxic side effects of inflammation.